Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications
TL;DR: The molecular pathways of mitochondria dynamics, their impairment under type 2 diabetes, and pharmaceutical approaches for targeting mitochondrial dynamics, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110 and 15-oxospiramilactone are discussed.
Abstract: Mitochondria play a key role in maintaining cellular metabolic homeostasis. These organelles have a high plasticity and are involved in dynamic processes such as mitochondrial fusion and fission, mitophagy and mitochondrial biogenesis. Type 2 diabetes is characterised by mitochondrial dysfunction, high production of reactive oxygen species (ROS) and low levels of ATP. Mitochondrial fusion is modulated by different proteins, including mitofusin-1 (MFN1), mitofusin-2 (MFN2) and optic atrophy (OPA-1), while fission is controlled by mitochondrial fission 1 (FIS1), dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF). PARKIN and (PTEN)-induced putative kinase 1 (PINK1) participate in the process of mitophagy, for which mitochondrial fission is necessary. In this review, we discuss the molecular pathways of mitochondrial dynamics, their impairment under type 2 diabetes, and pharmaceutical approaches for targeting mitochondrial dynamics, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110 and 15-oxospiramilactone. Furthermore, we discuss the pathophysiological implications of impaired mitochondrial dynamics, especially in type 2 diabetes.
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TL;DR: Empagliflozin improved diabetic myocardial structure and function, preserved cardiac microvascular barrier function and integrity, sustained eNOS phosphorylation and endothelium-dependent relaxation, as well as improved microvessel density and perfusion.
Abstract: Impaired cardiac microvascular function contributes to diabetic cardiovascular complications although effective therapy remains elusive. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor recently approved for treatment of type 2 diabetes, promotes glycosuria excretion and offers cardioprotective actions beyond its glucose-lowering effects. This study was designed to evaluate the effect of empagliflozin on cardiac microvascular injury in diabetes and the underlying mechanism involved with a focus on mitochondria. Our data revealed that empagliflozin improved diabetic myocardial structure and function, preserved cardiac microvascular barrier function and integrity, sustained eNOS phosphorylation and endothelium-dependent relaxation, as well as improved microvessel density and perfusion. Further study suggested that empagliflozin exerted its effects through inhibition of mitochondrial fission in an adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent manner. Empagliflozin restored AMP-to-ATP ratio to trigger AMPK activation, suppressed Drp1S616 phosphorylation, and increased Drp1S637 phosphorylation, ultimately leading to inhibition of mitochondrial fission. The empagliflozin-induced inhibition of mitochondrial fission preserved cardiac microvascular endothelial cell (CMEC) barrier function through suppressed mitochondrial reactive oxygen species (mtROS) production and subsequently oxidative stress to impede CMEC senescence. Empagliflozin-induced fission loss also favored angiogenesis by promoting CMEC migration through amelioration of F-actin depolymerization. Taken together, these results indicated the therapeutic promises of empagliflozin in the treatment of pathological microvascular changes in diabetes.
343 citations
Cites background from "Mitochondrial dynamics in type 2 di..."
...Besides, hyperglycemia-triggered mitochondrial fission may be lessened by mitophagy, a repair system for the mitochondrial homeostasis via timely clearance of the mitochondrial debris [15,53]....
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...Given the complexity of mitochondrial fission, and existence of several factors in fission regulation apart from Drp1 [53], the precise role of AMPK in the Fig....
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TL;DR: The latest findings on the intricate relationship between mitochondrial dynamics and ROS production are reviewed, focusing mainly on its role in malignant disease.
Abstract: Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.
323 citations
TL;DR: A general view about mitochondrial dysfunction in obesity is presented, including related alterations, such as inflammation, oxidative stress, and apoptosis, and focusing on the whole organism, covering alterations in peripheral tissues, BBB, and CNS.
311 citations
TL;DR: It is illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy and novel therapeutic strategies targeting the balance might provide survival advantage to microvasculature following IR stress.
Abstract: Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.
256 citations
Cites background from "Mitochondrial dynamics in type 2 di..."
...Mitochondrial fission and mitophagy are vital for control of mitochondrial quantity and quality [4, 11, 38]....
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TL;DR: In this article, a review of potential EDCs, their effects and mechanisms of action, epidemiological studies to analyze their effects on human health, bio-detection and chemical identification methods, difficulties in extrapolating experimental findings and studying endocrine disruptors in humans and recommendations for endocrinologists, individuals and policy makers will be discussed in view of the relevant literature.
Abstract: Endocrine Disrupting Chemicals (EDCs) are a global problem for environmental and human health. They are defined as "an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action". It is estimated that there are about 1000 chemicals with endocrine-acting properties. EDCs comprise pesticides, fungicides, industrial chemicals, plasticizers, nonylphenols, metals, pharmaceutical agents and phytoestrogens. Human exposure to EDCs mainly occurs by ingestion and to some extent by inhalation and dermal uptake. Most EDCs are lipophilic and bioaccumulate in the adipose tissue, thus they have a very long half-life in the body. It is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at later ages, and in some people do not present. Timing of exposure is of importance. Developing fetus and neonates are the most vulnerable to endocrine disruption. EDCs may interfere with synthesis, action and metabolism of sex steroid hormones that in turn cause developmental and fertility problems, infertility and hormone-sensitive cancers in women and men. Some EDCs exert obesogenic effects that result in disturbance in energy homeostasis. Interference with hypothalamo-pituitary-thyroid and adrenal axes has also been reported. In this review, potential EDCs, their effects and mechanisms of action, epidemiological studies to analyze their effects on human health, bio-detection and chemical identification methods, difficulties in extrapolating experimental findings and studying endocrine disruptors in humans and recommendations for endocrinologists, individuals and policy makers will be discussed in view of the relevant literature.
246 citations
Cites background from "Mitochondrial dynamics in type 2 di..."
...Phthalates levels showed a borderline significance with T2D in the same study....
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...However, mechanism(s) of EDCs leading to T2D are currently not well documented....
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...Human health Abbreviations AR Androgen Receptor AHR Aryl Hydrocarbon Receptor BPA Bisphenol A BMI Body Mass Index DDT Dichlorodiphenyltrichloroethane EDCs Endocrine Disrupting Chemicals EPA Environmental Protection Agency ER Estrogen Receptor GH Growth Hormone HPA Hypothalamo-Pituitary-Adrenal ISNT In Situ Nick Translation OCPs Organochlorinated Pesticides OVX Ovariectomized PPAR γ: Peroxisome Proliferator-Activated Receptor γ POPs Persistent Organochlorine Pollutants PI3K Phosphatidylinositol 3 Kinase PCBs Polychlorinated Biphenyls COMET Single Cell Gel Electrophoresis Assay NIS Sodium-Iodide Symporter Channel SCSA Sperm Chromatin Structure Assay TUNEL Terminal Transferase dUTP Nick End Labeling TCDD Tetrachlorodibenzo-p-Dioxin T4 Thyroxine T3 Triiodothyronine T2D Type 2 Diabetes * Fahrettin Kelestimur fahrettin.kelestemur@yeditepe.edu.tr; fktimur@erciyes.edu.tr Bayram Yilmaz byilmaz@yeditepe.edu.tr 1 Department of Physiology, Faculty ofMedicine, Yeditepe University, Istanbul, Turkey 2 Department of Internal Medicine, Faculty of Medicine, Yeditepe University, Istanbul, Turkey 3 Department of Physiology, Faculty of Medicine, Inonu University, Malatya, Turkey 4 Department of Endocrinology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey...
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...However, there may be direct effects of these chemicals leading to interference with glucose metabolism and finally T2D as discussed in several epidemiological and experimental studies, above....
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...It should also be noted that genetic predisposition, lifestyle factors such as lack of exercise and weight gain and bioaccumulation of POPS in human body may all contribute to increased risk of developing T2D....
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References
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TL;DR: This integrating paradigm provides a new conceptual framework for future research and drug discovery in diabetes-specific microvascular disease and seems to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain.
Abstract: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.
8,289 citations
"Mitochondrial dynamics in type 2 di..." refers background in this paper
...Mitochondria biogenesis contributes to modulate the energy balance, and an enhanced production of ROS by the electron transport chain under hyperglycemic conditions is thought to exacerbate pathological pathways, leading to diabetic microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (stroke, myocardial ischemia) complications [3]....
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TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.
Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
7,997 citations
TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.
4,529 citations
"Mitochondrial dynamics in type 2 di..." refers background in this paper
...In the case of mitochondria, this mechanism is known as mitophagy [26]....
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TL;DR: Pulse chase and arrest of autophagy at the pre‐proteolysis stage reveal that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagic.
Abstract: Accumulation of depolarized mitochondria within β-cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a ‘kiss and run' pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (Δψm) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non-fusing mitochondria that were found to have reduced Δψm and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1K38A or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre-proteolysis stage reveal that before autophagy mitochondria lose Δψm and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.
2,642 citations
"Mitochondrial dynamics in type 2 di..." refers background in this paper
...Different mechanisms have been used by mitochondria to control their homeostasis; for example, mitochondrial fusion and fission are key to the repair of mitochondrial damaged components, allowing the exchange of material between damaged and non-damaged mitochondria via the fusion process, or segregation of damaged components via the fission process [4,5]....
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TL;DR: Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L).
Abstract: Mitophagy is the selective elimination of mitochondria through autophagy Recent studies have uncovered the molecular mechanisms mediating mitophagy in yeast and mammalian cells and have revealed that the dysregulation of one of these mechanisms — the PINK1–parkin-mediated signalling pathway — may contribute to Parkinson's disease
2,608 citations
"Mitochondrial dynamics in type 2 di..." refers background in this paper
...In this sense, mitochondrial fission plays a central role, since mitophagy is preceded by mitochondrial division, which generates individual mitochondrial fragments of manageable size for encapsulation [8] (Fig....
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